Neuroimmune Processes and Neuroplasticity in Chronic Spinal Cord Injury

慢性脊髓损伤的神经免疫过程和神经可塑性

• 批准号: 8466770
• 负责人: Harold David Shine
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466770
• 关键词: Acute; Address; Axon; Belief; Biology; Biomedical Technology; Blocking Antibodies; Candidate Disease Gene; Chronic; Contralateral; Corticospinal Tracts; Distal; Environment; Gene Delivery; Gene Expression; Gene Proteins; Goals; Growth Factor; Immune; Immune Cell Activation; Immune response; Immune system; Immunoassay; Injury; Ipsilateral; Knowledge; Lead; Lesion; Leukocytes; Lipopolysaccharides; Measures; Mediating; Microglia; Modeling; Molecular; Motor Neurons; Natural regeneration; Nerve Degeneration; Neuroimmunomodulation; Neuronal Plasticity; Neurotrophin 3; Nude Rats; Patients; Phase; Play; Process; Rattus; Recovery; Role; Site; Source; Spinal Cord; Spinal Cord Lesions; Spinal cord injury; Spinal cord injury patients; T-Lymphocyte; Testing; Time; Tissue-Specific Gene Expression; Wallerian Degeneration; War; Work; Wound Healing; arm; axon growth; axon regeneration; axonal sprouting; base; central nervous system injury; chemokine; clinically significant; cytokine; immunosuppressed; injured; nerve injury; neurotrophic factor; peace; prevent; protein expression; reconstitution; release factor; repaired; research study; response

DESCRIPTION (provided by applicant): Over-expression of Neurotrophin-3 (NT-3) in lumbar motoneurons induces axons to grow from the contralateral corticospinal tract (CST) towards the source of NT-3 in rats but only if the CST ipsilateral to the transduced motoneurons is lesioned and if the NT-3 over-expression is coincident with the time of lesion. If NT-3 over-expression is delayed 4m after the lesion there is no axonal growth suggesting that at least one factor associated with the acute phase of the CST injury is involved. If the rats with acute CST lesions were immunosuppressed axonal growth in response to NT-3 is blocked. When the experiment was repeated in athymic nude (AN) rats there was no axonal growth in response to NT-3. If the immune response is re-activated in chronically lesioned rats with systemic lipopolysaccharide (LPS) NT-3 will induce axonal growth. This is the first demonstration of inducing axonal growth with neurotrophins in achronically lesioned CNS. These observations suggest that NT-3-induced axonal growth requires processes associated with immune-mediated wound healing; specifically activated T- cells. The goals of this project are to identify the factor or factors associated with immune-mediated wound healing and test them in conjunction with NT-3 in our model of chronic spinal cord injury. The specific aims are to: (1) verify the role of T-cells in NT-3-induced axonal growth, identify the T-cell subtype responsible, (2) determine the role of microglial activation in this process, and (3) identify genes and proteins differentially expressed in conditions that support NT-3 induced axonal growth compared to those that do not using qPCR and protein expression using multiplex array immunoassays in AN rats. Our results show that neuroplasticity can be induced in the chronically injured spinal cord distal to the lesion site. This neuroplasticity is likely induced by the presence of NT-3 and a factor, or factors, associated with immune-mediated wound healing. If the identity of the factor(s) associated with the acute injury can be identified then it may be possible to recapitulate the acute environment in patients with chronic spinal cord injuries to induce neuroplasticity in spared axonal tracts. Two-thirds of spinal cord injury patients have incomplete cord transections so strategies to enhance the function of the remaining connections by enabling the inherent plasticity of the CNS may provide improvement in function of patients with chronic spinal cord injury.

描述（由申请人提供）： 腰部运动神经元中神经营养蛋白3（NT-3）的过表达可诱导轴突从对侧皮质脊髓段（CST）向大鼠NT-3的来源增长，但仅当CST iPsil ipsilatial to the dypsield of to to tods to tod to tods to tods to tods to tods to tods tod tods tods toded tods toded toded toded toded toded tod toded剂量的运动神经元。 NT-3的过表达与病变的时间一致。如果NT-3过表达在病变后延迟4M，则没有轴突生长表明至少涉及与CST损伤的急性相关的一个因子。如果急性CST病变的大鼠被免疫抑制轴突生长，则响应于NT-3。当实验在无胸腺裸体（AN）大鼠中重复时，对NT-3的响应没有轴突生长。如果在具有全身性脂多糖（LPS）NT-3的慢性病变大鼠中重新激活免疫反应，将诱导轴突生长。这是诱导伴有神经营养蛋白的轴突生长的首次证明，在ac体病变的中枢神经系统中。这些观察结果表明，NT-3诱导的轴突生长需要与免疫介导的伤口愈合相关的过程。专门激活的T细胞。该项目的目标是确定与免疫介导的伤口愈合相关的因素或因素，并在我们的慢性脊髓损伤模型中与NT-3结合进行测试。具体目的是：（1）验证T细胞在NT-3诱导的轴突生长中的作用，确定负责的T细胞亚型，（2）确定小胶质激活在此过程中的作用，以及（3）与不使用QPCR和蛋白质表达的轴突生长相比，在支持NT-3诱导轴突生长的条件下差异表达的基因和蛋白质表达。我们的结果表明，可以在病变部位远端的长期受伤的脊髓中诱导神经可塑性。这种神经塑性可能是由NT-3的存在以及与免疫介导的伤口愈合相关的因素或因素引起的。如果可以确定与急性损伤相关的因子的身份，则有可能概括慢性脊髓损伤患者的急性环境，以诱导保存的轴突段中的神经可塑性。三分之二的脊髓损伤患者患有不完全的绳索过渡，因此通过实现CNS的固有可塑性来增强其余连接功能的策略可能会改善慢性脊髓损伤患者的功能。